Selegiline, including its acid addition salt forms, has heretofore been known to be useful for veterinary and clinical purposes because of its neuronal-protective or neuronal-regenerative effects and is dopaminergic effects, i.e., its selective inhibition of the enzymatic degradation of dopamine by monoamine oxidase B. Selegiline, i.e., R-(-)-N-methyl-N-(prop-2-ynyl)-2-aminophenylpropane, also known as L-(-)-deprenyl or R-(-)-deprenyl, has the following structural formula: ##STR1##
The discovery of selegiline initially represented an important therapeutic improvement over known non-selective monoamine oxidase inhibitors, e.g., tranylcypromine. Tranylcypromine was introduced more than thirty years ago for the treatment of depression, but was subsequently withdrawn from clinical use because of a severe hypertensive side effect, the so-called "cheese effect". Tranylcyproamine was non-selective with respect to the two distinct monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). In particular, the cDNAs encoding these enzymes show different promoter regions and distinct exon portions, indicating they are encoded independently at different gene positions, and analysis of the two proteins has shown differences in their respective amino acid sequences.
The relative selectivity of selegiline in the inhibition of MAO-B is important to its safety profile following oral administration. The "cheese effect" and resulting acute toxicity of tranylcypromine arises from its inhibition of MAO-A, which interferes with the metabolism of tyramine. Tyramine is normally metabolized in the gastrointestinal tract by MAO-A. However, when MAO-A is inhibited, tyramine absorption is increased following consumption of tyramine-containing foods such as cheese, beer, herring, etc. This results in the release of catecholamines which can precipitate a hypertensive crisis, producing the "cheese effect." This effect is characterized by Goodman and Gilman as the most serious toxic effect associated with MAO-A inhibitors. Although selegiline is a selective inhibitor of MAO-B at certain dosages and conditions, it produces undesirable inhibition of MAO-A when administered under other conditions, e.g., higher doses. Thus, tyramine sensitivity and the risk of hypertensive crisis increases following oral administration to a human of oral doses of selegiline greater than about 10 mg.
More recently, selegiline has been determined to exhibit direct neuronal effects that may be independent of its MAO-B inhibitory activity. Thus, selegiline is known to be useful for treating diseases and condition associated both with the aforedescribed dopaminergic effect and the more recently characterized neuronal protective or regenerative effect.
Because of these significant pharmacological effects, selegiline is known to be useful in a significant variety of diseases and conditions. For example, U.S. Pat. No. 4,861,800 (Buyske) discloses the use of selegiline in the treatment of depression, Alzheimer's disease and Parkinson's disease, particularly through the use of transdermal dosage forms, including ointments, creams and patches. U.S. Pat. No. 5,242,950 (Hastings) discloses the use of selegiline in the treatment of macular degeneration. U.S. Pat. No. 5,151,449 (Milgram) discloses the use of selegiline in the treatment of age-dependent degeneracies, including age-dependent weight loss, the loss of renal function and the loss of cognitive function, including spatial learning ability. U.S. Pat. No. 5,276,057 (Milgram and Stevens) discloses the use of selegiline in the treatment of immune system dysfunction. U.S. Pat. No. 5,151,419 discloses the use of selegiline in the treatment of schizophrenia. PCT Published Application WO 92/17169 and U.S. Pat. No. 5,444,095 disclose the use of selegiline in the treatment of neuromuscular and neurodegenerative disease and in the treatment of CNS injury due to hypoxia, hypoglycemia, ischemic stroke or trauma; neurotoxic agents (e.g. MPTP); or amyotrophic lateral sclerosis. (ALS). Selegiline provides neuroprotection or neuronal rescue, by one or more mechanisms, for example, by reducing oxidative neuronal damage, increasing the amount of the enzyme superoxide dismutase, and/or reducing dopamine catabolism. PCT Published Application WO 92/17169 discloses that selegiline acts by directly maintaining, preventing loss of, and/or assisting in, the nerve function of animals.
In addition, selegiline has been disclosed as being useful in the treatment of glaucoma and impotence. See Trope, G. E., et al, "(-)-Deprenyl Improves Visual Function in Glaucoma Patients," Investigative Ophthalmology & Visual Science, 34:2178 (Mar. 15, 1994). See also, Knoll, J., et al, "Long-lasting true aphrodisiac effect of (-)-deprenyl in sluggish old male rats," Mod. Problems Pharmacopsychiatry 19:135-153 (1983) and "Sexually low performing male rats die earlier than their high performing peers and selegiline eliminates this difference," Life Sciences 54:1047-1957 (1994).
U.S. Pat. No. 5,192,808 (Ruehl) discloses the use of selegiline in the treatment of pituitary-dependent Cushing's disease. For example, in Cushing's disease, the selegiline-like therapeutic effects may be observed in any of a number of common tests used in diagnosing and monitoring the disease (for a discussion of specific tests see, U.S. Pat. No. 5,192,808).
Selegiline has also been demonstrated to have clinical efficacy in the treatment attention-deficit, hyperactivity disease (ADHD) and Tourette's Syndrome (TS). See Feigin, A., "A Double-Blind, Placebo-Controlled, Cross-over study of Deprenyl in Children with Tourette's Syndrome (TS) and attention-Deficit Hyperactivity Disorder (ADHD)," Neurology 45 (Suppl. 4):337P (April 1995).
Selegiline is known to be useful when administered to a subject through a wide variety of routes of administration and dosage forms. For example U.S. Pat. No. 4,812,481 (Degussa AG) discloses the use of concomitant selegiline-amantadine therapy in which selegiline is used with amantadine in oral, peroral, enteral, pulmonary, rectal, nasal, vaginal, lingual, intravenous, intraarterial, intracardial, intramuscular, intraperitoneal, intracutaneous, and subcutaneous formulations.
Buccal and sublingual compositions of selegiline have been described. U.S. Pat. No. 5,192,550 (Alza Corporation) describes a dosage form into which selegiline may be incorporated comprising an outer wall with one or more pores in which the wall is impermeable to deprenyl, but permeable to external fluids. This dosage form is disclosed to be applicable for oral, sublingual or buccal administration. Similarly, U.S. Pat. No. 5,387,615 discloses a variety of selegiline compositions, including tablets, pills, capsules, powders, aerosols, suppositories, skin patches, parenterals, and oral liquids, including oil-aqueous suspensions, solutions, and emulsions. Further disclosed therein are selegiline-containing sustained release (long acting) formulations and devices.
Selegiline is metabolized in vivo in humans into three main metabolites: desmethylselegiline, amphetamine and methamphetamine. One of the metabolites, desmethylselegiline, does in fact inhibit monoamine oxidase B. However, compared to selegiline, inhibitory activity is exceedingly weak. For example, experiments performed in vitro using human platelets have indicated that desmethylselegiline is 68 times less potent than selegiline in inhibiting MAO-B. Similarly, results obtained from mitochondrial-rich fractions from rat cortex and rat brain have indicated that selegiline is approximately 50 times more potent than its desmethyl metabolite as an MAO-B inhibitor and is approximately equal in terms of specificity for MAO-B relative to MAO-A.
The potency of desmethylselegiline as an MAO-B inhibitor in vivo has been reported by Heinonen, E. H., et al., ("Desmethylselegiline, a metabolite of selegiline, is an irreversible inhibitor of MAO-B in human subjects," referenced in Academic Dissertation "Selegiline in the Treatment of Parkinson's Disease," from Research Reports from the Department of Neurology, University of Turku, Turku, Finland, No. 33 (1995), pp. 59-61). According to Heinonen, desmethylselegiline appears to have only one-fifth of the MAO-B inhibitory effect of selegiline in vivo, i.e., a dose of 10 mg of desmethylselegiline would be required to have the same MAO-B effect as 1.8 mg of selegiline.
The two other principal metabolites of selegiline, amphetamine and methampbetamine, are both known to have neurotoxic effects and are therapeutically undesirable (see e.g., Ryan et al., "Histological and ultrastructural evidence that D-amphetamine causes degeneration in neostriatum and frontal cortex of rats," Brain Res. 518:76-77 (1990); Pu et al., "The effects of amfonelic acid, a dopamine uptake inhibitor, on methamphetamine-induced dopaminergic terminal degeneration and astrocytic response in rat striatum," Brain Res. 649:217-224 (1994); Ellison, "Continuous amphetamine and cocaine have similar neurotoxic effects in lateral habenular nucleus and fasciculus retroflexus," Brain Res. 598:353-356 (1992)).
The present invention is based upon the discovery that certain diseases and conditions for which selegiline is known to be useful are surprisingly and unexpectedly more advantageously treated by administering selegiline buccally or sublingually rather than by administering selegiline using prior art methods, e.g., oral administration. Accordingly, the novel methods disclosed herein produce enhanced therapeutic effects.